Following the scientific literature on the relationship between plasma homocysteine and health has been something of a roller coaster ride over the last few years. The brief introduction is that elevated homocysteine levels have been associated with an increased risk of health conditions such as stroke, heart disease, and cognitive decline – yet randomized controlled trials (RCTs) have had mixed results. So what’s going on here?

Case in point: Nie et al. published a meta-analysis of prospective cohort studies that showed a significant association between elevated homocysteine concentrations and an increased risk of cognitive decline. Shortly after that, van der Zwaluw and colleagues published the results of a 2-year long RCT comparing the effect of a supplement with folic acid and vitamin B12 to placebo on measures of cognitive decline and reported no overall benefit of vitamin supplementation.

Regular readers of TalkingNutrition probably know that we are very strong proponents of the idea that nutritional status matters, and that nutrient status is a very important factor that we rarely account for when designing intervention studies in nutrition. While van der Zwaluw et al. selected patients with elevated levels of homocysteine, they did not set any criteria about nutrient status markers, like serum folate and vitamin B12. Participants in this study had serum folate concentrations on the high end of normal (~19 nmol/L), yet their median B12 status was not too far above the cutoff for deficiency. An interesting finding that didn’t really get enough attention (in my opinion, anyway) is that those participants with the lowest holo-TC concentrations (a biomarker of vitamin B12 status) had a significantly greater improvement in memory performance compared to those taking placebo. I’d be willing to speculate that if they recruited subjects with a lower folate status, the overall observed effects on cognition would have been even greater.

But why would that matter? Because nutrient supplementation provides the most benefit for those with the poorest nutrient intakes, and ultimately the lowest nutrient status. This sentiment is echoed in prospective cohort studies: Nie et al. found that B-vitamin intake was a significant cofounder in determining the relationship between homocysteine and cognitive decline.

These data once again highlight the importance of nutrient status in designing and interpreting RCTs in nutrition. We as nutrition scientists need to do a better job of considering the nutrient status of patients at baseline when looking to measure effects of nutrient supplementation through RCTs.